Delivery of therapeutic agents to their site of action within the body is a challenge for most pharmaceutical agents. Oral administration requires that the agent be stable at the low pH of the stomach and readily absorbed in the intestine at a neutral pH. Administration of pharmaceutical agents by injection abrogates the need for agents that are stable through a wide pH range; however, a substantial portion of the agent may be eliminated from the circulation by the liver in what is known as the “first pass effect.” Moreover, any route of injection (e.g. intravenous, subcutaneous) is a less desirable route of administration as compared to less invasive methods (e.g., topical, oral). This is especially true for agents that must be delivered on a relatively frequent basis, as injections are painful and require intervention of or training by a trained medical professional, sterile procedures, and methods to both obtain and discard needles in a safe manner.
Topical administration of pharmaceutical agents provides an ideal route of administration. The skin is substantially homogeneous, as compared to the digestive tract. Topical administration requires no special training or equipment, and is painless. However, uptake of pharmaceutical agents through the skin is limited due to the structure and function of the skin as a protective barrier.
Mammalian skin consists of two major, distinct layers, the epidermis and the dermis. The epidermis is comprised of the stratum corneum, the stratum granulosum, the stratum spinosum, and the stratum basale, with the stratum corneum being at the surface of the skin and the stratum basale being the deepest portion of the epidermis. The epidermis is between 50 μm and 0.2 mm thick, depending on its location on the body.
Beneath the epidermis is the dermis, which is significantly thicker than the epidermis. The dermis is primarily composed of collagen in the form of fibrous bundles. The collagenous bundles provide support for, inter alia, blood vessels, lymph capillaries, glands, nerve endings and immunologically active cells.
One of the major functions of the skin as an organ is to regulate the entry of substances into the body. The principal permeability barrier of the skin is provided by the stratum corneum, which is formed from many layers of cells in various states of differentiation. The spaces between cells in the stratum corneum is filled with different lipids arranged in lattice-like formations which provide seals to further enhance the skin's permeability barrier.
The permeability barrier provided by the skin is largely impermeable to molecules having molecular weight greater than about 750 Da. For larger molecules to cross the skin's permeability barrier, mechanisms other than normal osmosis must be used.
Several factors determine the permeability of the skin to administered agents. These factors include the characteristics of the treated skin, the characteristics of the delivery agent, interactions between both the drug and delivery agent and the drug and skin, the dosage of the drug applied, the form of treatment, and the post treatment regimen. To selectively target the epidermis and/or dermis, it is sometimes possible to formulate a composition with one or more penetration enhancers that enable penetration of the drug to a preselected stratum.
Nucleic acid based therapeutic agents are becoming more widely used as various mechanisms of modulating RNA and protein expression are discovered. A number of antisense oligonucleotide therapeutic agents are currently in clinical trials, and one antisense oligonucleotide based drug has been approved for use in humans (Vitravene). These oligonucleotides are single stranded molecules that are modified to increase their stability and/or affinity for their target RNA. More recently, the use of double stranded nucleic acid agents, known as small interfering RNAs (siRNAs) for the modulation of mRNA and protein expression has been described (Guo and Kempheus, Cell, 81:611-620, 1995). Montgomery et al. have shown that the primary interference effects of dsRNA are posttranscriptional (Montgomery et al., Proc. Natl. Acad. Sci. USA, 95:15502-15507, 1998). The posttranscriptional antisense mechanism defined in Caenorhabditis elegans resulting from exposure to double-stranded RNA (dsRNA) has since been designated RNA interference (RNAi). Antisense, RNAi and microRNA mechanisms rely substantially on specific base pairing of the nucleic acid therapeutic agent with the target mRNA of interest allowing for modulation of a specific target, typically decreasing the expression of an mRNA, subsequently reducing the expression of the corresponding protein. Nucleic acid based therapeutic agents that do not rely fully on base pairing to the target are also known, such as aptamers, G4 core sequences and ribozymes.
To date, nucleic acid based therapeutics have been delivered by injection, subcutaneously, intravenously or intravitreally. Both intravenous and intravetreal administration require the use of trained personnel to deliver the therapeutic agent. Although individuals may be taught to self-administer compositions by subcutaneous injection, it is not a preferred route of administration as discussed above. This places a practical limitation on the use of nucleic acid based therapeutics for relatively severe conditions (e.g. cancer) such that the individual to be treated is willing to undergo administration of the therapeutic agent by such an invasive manner. The ability to deliver nucleic acid therapeutic agents by non-invasive methods, such as topical administration, would make nucleic acid based therapeutics and agents useful for a far larger number of applications, including cosmetic uses (e.g. hair removal).